Project Summary/Abstract: Juvenile rheumatoid (or idiopathic) arthritis (JRA/JIA) is the most common cause of childhood disability. Even the mildest form of the disease carries a significant risk of joint deformation and loss of function that foreshadows lifelong discomfort and disability. The disease affects 1 child in every 200 under the age of 16. Controlling the disease in early childhood is important to prevent the deformity and later disability in children with JRA/JIA. However, the current treatment paradigm mandating earlier use of aggressive, anti-inflammatory drugs has potential harmful side effects making it imperative that we develop measures that can detect impending disease flares and develop better drugs for treatment with fewer side effects. In order to achieve these goals we need to better understand the development of the disease. Presently, we do not know what triggers the abnormal immune activity in JIA that can lead to serious damage to joints, eyes, and other vital organs, and there are no markers in the blood or genes of children with arthritis that can help us to follow disease activity or to predict JIA outcome. Recent discovery of an antibody to the DEK protein in some children with JIA and related diseases holds great promise for improving our knowledge of how these conditions begin and how they might be treated more effectively. We recently identified DEK protein and antibodies in synovial fluids from patients. We also found that DEK protein is secreted by activated human macrophages by a process that is capable of eliciting antibodies against the DEK protein. The secretion of DEK is stimulated by Interleukin-8, a protein that helps to recruit immune cells to an area of inflammation. In addition, dexamethasone and cyclosporin, two powerful anti-inflammatory medications used to treat autoimmune diseases, can block DEK secretion. We have also seen that the DEK protein itself can attract immune cells to an area of inflammation and, in this way may, increase the severity of the immune reaction. Now we suggest to investigate in details the way DEK attracts immune cells by identifying the potential binding receptor/s for DEK. To identify the binding receptor/s to DEK we will perform in vitro migration assays using specific receptors inhibitors, immunoprecipitation and co-localization assays. To investigate DEK contribution to the development of the disease will use several known animal models for arthritis assess the effect of DEK protein and antibodies on the development of the disease. These insights are very important to our ability to develop a new strategy to the diagnosis/treatment of JIA, and to improve the present and future health of children with arthritis and related diseases.